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Molecular and Cellular Biology, May 2005, p. 4237-4249, Vol. 25, No. 10
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.10.4237-4249.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

The S1P2 Receptor Negatively Regulates Platelet-Derived Growth Factor-Induced Motility and Proliferation

Sravan K. Goparaju,1,{dagger} Puneet S. Jolly,1,2,{dagger} Kenneth R. Watterson,1 Meryem Bektas,1 Sergio Alvarez,1 Sukumar Sarkar,1 Lin Mel,1 Isao Ishii,3 Jerold Chun,4 Sheldon Milstien,5 and Sarah Spiegel1*

Department of Biochemistry, Virginia Commonwealth University Medical Center, Richmond, Virginia 23298-0614,1 Department of Biochemistry and Molecular Biology, Georgetown University Medical Center, Washington, D.C. 20007,2 Department of Molecular Genetics, National Institute of Neuroscience, Tokyo 187-8502, Japan,3 Department of Molecular Biology, Helen L. Dorris Neurological and Psychiatric Disorder Institute, Scripps Research Institute, La Jolla, California 92037,4 Laboratory of Cellular and Molecular Regulation, National Institute of Mental Health, Bethesda, Maryland 208925

Received 29 September 2004/ Returned for modification 28 October 2004/ Accepted 6 February 2005

Sphingosine-1-phosphate (S1P), a bioactive sphingolipid metabolite, is the ligand for five specific G protein-coupled receptors, named S1P1 to S1P5. In this study, we found that cross-communication between platelet-derived growth factor receptor and S1P2 serves as a negative damper of PDGF functions. Deletion of the S1P2 receptor dramatically increased migration of mouse embryonic fibroblasts toward S1P, serum, and PDGF but not fibronectin. This enhanced migration was dependent on expression of S1P1 and sphingosine kinase 1 (SphK1), the enzyme that produces S1P, as revealed by downregulation of their expression with antisense RNA and small interfering RNA, respectively. Although S1P2 deletion had no significant effect on tyrosine phosphorylation of the PDGF receptors or activation of extracellular signal-regulated kinase 1/2 or Akt induced by PDGF, it reduced sustained PDGF-dependent p38 phosphorylation and markedly enhanced Rac activation. Surprisingly, S1P2-null cells not only exhibited enhanced proliferation but also markedly increased SphK1 expression and activity. Conversely, reintroduction of S1P2 reduced DNA synthesis and expression of SphK1. Thus, S1P2 serves as a negative regulator of PDGF-induced migration and proliferation as well as SphK1 expression. Our results suggest that a complex interplay between PDGFR and S1P receptors determines their functions.

* Corresponding author. Mailing address: Department of Biochemistry, Virginia Commonwealth University Medical Center, 1101 E. Marshall Street, Room 2-011, Sanger Hall, Richmond, VA 23298-0614. Phone: (804) 828-9330. Fax: (804) 828-8999. E-mail: sspiegel{at}vcu.edu.

{dagger} These authors contributed equally.

Molecular and Cellular Biology, May 2005, p. 4237-4249, Vol. 25, No. 10
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.10.4237-4249.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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